Department of Urology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
Mediators Inflamm. 2021 Oct 4;2021:1791222. doi: 10.1155/2021/1791222. eCollection 2021.
Notch1 signaling regulates microglia activation, which promotes neuroinflammation. Neuroinflammation plays an essential role in various kinds of pain sensation, including bladder-related pain in bladder pain syndrome/interstitial cystitis (BPS/IC). However, the impact of Notch1 signaling on mechanical allodynia in cyclophosphamide- (CYP-) induced cystitis is unclear. This study is aimed at determining whether and how Notch1 signaling modulates mechanical allodynia of CYP-induced cystitis.
CYP was peritoneally injected to establish a bladder pain syndrome/interstitial cystitis (BPS/IC) rat model. A -secretase inhibitor, DAPT, was intrathecally injected to modulate Notch1 signaling indirectly. Mechanical withdrawal threshold in the lower abdomen was measured with von Frey filaments using the up-down method. The expression of Notch1 signaling, Iba-1, OX-42, TNF-, and IL-1 in the L6-S1 spinal dorsal horn (SDH) was measured with Western blotting analysis and immunofluorescence staining.
Notch1 and Notch intracellular domain (NICD) were both upregulated in the SDH of the cystitis group. Moreover, the expression of Notch1 and NICD was negatively correlated with the mechanical withdrawal threshold of the cystitis rats. Furthermore, treatment with DAPT attenuated mechanical allodynia in CYP-induced cystitis and inhibited microglia activation, leading to decreased production of TNF- and IL-1.
Notch1 signaling contributes to mechanical allodynia associated with CYP-induced cystitis by promoting microglia activation and neuroinflammation. Our study showed that inhibition of Notch1 signaling might have therapeutic value for treating pain symptoms in BPS/IC.
Notch1 信号通路调节小胶质细胞的激活，进而促进神经炎症。神经炎症在各种疼痛感觉中发挥着重要作用，包括在膀胱疼痛综合征/间质性膀胱炎（BPS/IC）中与膀胱相关的疼痛。然而，Notch1 信号通路对环磷酰胺（CYP）诱导的膀胱炎中机械性痛觉过敏的影响尚不清楚。本研究旨在确定 Notch1 信号通路是否以及如何调节 CYP 诱导的膀胱炎中的机械性痛觉过敏。
通过腹腔注射 CYP 建立 BPS/IC 大鼠模型。鞘内注射 γ-分泌酶抑制剂 DAPT 间接调节 Notch1 信号通路。采用 von Frey 纤维丝采用上下法测量下腹的机械性缩腹阈值。采用 Western blot 分析和免疫荧光染色检测 L6-S1 脊髓背角（SDH）中 Notch1 信号、Iba-1、OX-42、TNF-α 和 IL-1 的表达。
在膀胱炎组的 SDH 中，Notch1 和 Notch 细胞内结构域（NICD）均上调。此外，Notch1 和 NICD 的表达与膀胱炎大鼠的机械性缩腹阈值呈负相关。此外，DAPT 治疗可减轻 CYP 诱导的膀胱炎中的机械性痛觉过敏，并抑制小胶质细胞激活，从而减少 TNF-α 和 IL-1 的产生。
Notch1 信号通路通过促进小胶质细胞激活和神经炎症，导致与 CYP 诱导的膀胱炎相关的机械性痛觉过敏。我们的研究表明，抑制 Notch1 信号通路可能对治疗 BPS/IC 中的疼痛症状具有治疗价值。
